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WO1993019075A1 - Derives acides phosphoniques antiviraux d'analogues de purine - Google Patents

Derives acides phosphoniques antiviraux d'analogues de purine Download PDF

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Publication number
WO1993019075A1
WO1993019075A1 PCT/GB1993/000560 GB9300560W WO9319075A1 WO 1993019075 A1 WO1993019075 A1 WO 1993019075A1 GB 9300560 W GB9300560 W GB 9300560W WO 9319075 A1 WO9319075 A1 WO 9319075A1
Authority
WO
WIPO (PCT)
Prior art keywords
hydrogen
compound according
compound
formula
amino
Prior art date
Application number
PCT/GB1993/000560
Other languages
English (en)
Inventor
Michael Raymond Harnden
Stuart Bailey
Halina Teresa Serafinowska
Original Assignee
Smithkline Beecham Plc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to EP93906699A priority Critical patent/EP0631583A1/fr
Priority to JP5516084A priority patent/JPH07504666A/ja
Priority to KR1019940703269A priority patent/KR950701638A/ko
Publication of WO1993019075A1 publication Critical patent/WO1993019075A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • the present invention relates to novel compounds which are of potential use as antiviral agents, to processes for their preparation and to their use as pharmaceuticals.
  • EP-A-319228 and EP-A-353955 (Beecham Group p.lc.) disclose a group of purine derivatives containing a 9-[2-(phosphonomethoxy)alkoxy] substituent, which are described as having antiviral activity.
  • EP-A-206459 (Ceskoslovenska akademie ved) discloses a group of
  • Particular compounds of interest are adenine or guanine having a 9-substituent as follows:
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof:
  • X is -CH 2 O, -CH 2 or -CH(CH 2 OR 6 )O where R 6 is hydrogen or acyl;
  • R 1 is hydroxy or amino
  • R 2 is amino or hydrogen
  • R 3 is hydrogen or, when X is CH 2 O and Y is O, R 3 may be CH 2 OR 7 where R 7 is hydrogen or acyl;
  • R 4 and R 5 are both phenyl, 4-bromophenyl, 4-methylphenyl, 4-methoxyphenyl, 2- acetoxyphenyl or 2-methylphenyl.
  • the compound of formula (I) is a 2,6-diaminopurine derivative.
  • the compound of formula (I) is a guanine or adenine derivative.
  • R 4 and R 5 are preferably both phenyl.
  • Suitable examples of R 6 /R 7 when acyl include carboxylic acyl, such as C 1-7 alkanoyl and benzoyl optionally substituted in the phenyl ring by one, two or three groups or atoms selected from halogen, such as fluoro, chloro, bromo, and C 1-4 alkyl or C 1-4 alkoxy wherein the alkyl moiety is selected from methyl, ethyl, n- and iso-propyl, n-, sec-, iso- and rert-butyl.
  • Preferred acyl groups include acetyl, propionyl, butyryl, heptanoyl and hexanoyl.
  • X is -CH 2 O and R 3 is hydrogen.
  • X is -CH 2 O and R 3 is CH 2 OR 7 as defined.
  • X is -CH 2 (CH 2 OR 6 )O as defined and R 3 is hydrogen .
  • X is -CH 2 and R 3 is hydrogen.
  • X is -CH 2 and R 3 is CH 2 OR 7 as defined.
  • Y is preferably O.
  • Examples of pharmaceutically acceptable salts of the compound of formula (I) are acid addition salts formed with a pharmaceutically acceptable acid such as hydrochloric acid, orthophosphonc acid and sulphuric acid.
  • Pharmaceutically acceptable salts also include those formed with organic bases, preferably with amines, such as
  • ethanolamines or diamines ethanolamines or diamines
  • alkali metals such as sodium and potassium
  • the compounds of formula (I) including their alkali metal salts may form solvates such as hydrates and these are included wherever a compound of formula (I) or a salt thereof is herein referred to.
  • the invention also provides a process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, which process comprises reacting a compound of formula (II):
  • R 4 OH and R 5 OH and R 1 , R 2 , and R 3 are as defined in formula (I), and thereafter optionally forming a pharmaceutically acceptable salt thereof.
  • the reaction takes place in a suitable inert solvent such as dichloromethane at temperatures with cooling 0 to 3°C, under an inert atmosphere.
  • a suitable inert solvent such as dichloromethane at temperatures with cooling 0 to 3°C, under an inert atmosphere.
  • R 1 /R 2 /R 3 may be protected. Suitable examples of protecting groups and their removal, are as described in EP-A-242482. A particularly suitable protecting group forR 3 when other than hydrogen is the t-butyldiphenylsilyl group removable by conventional methods.
  • the compounds of formula (ll) may be generated from the corresponding compounds of formula (I), but wherein R 4 /R 5 is replaced by an ethyl group, by treatment with bromotrimethylsilane in dichloromethane followed by chlorination with PCI 5 in dichloromethane: carbon tetrachloride.
  • R 4 /R 5 ethyl compounds of the formula (I) are prepared as described in EP-A-313289 and the aforementioned publications, the subject matter of which are incorporated herein by reference.
  • R 6 /R 7 is hydroxy, appropriate selective protection may be required, eg using acetate.
  • compositions may be prepared in conventional manner, for example, in the case of acid addition salts, by reaction with the appropriate organic or inorganic acid.
  • the invention provides a process for the preparation of a compound of formula (I) wherein R 6 /R 7 is hydrogen which process comprises the deprotection of a corresponding compound of formula (I) wherein R 8 /R 9 . is protected hydroxy.
  • Methods for deprotection, are conventional for the protecting group concerned.
  • the compounds of the invention are of potential use in the treatment of infections caused by viruses, in particular DNA viruses and retroviruses.
  • DN A viruses include herpesviruses such as herpes simplex types 1 and 2, varicella-zoster virus, Epstein-Barr virus and cytomegalovirus.
  • retroviruses include lentiviruses such as visna virus and human immunodeficiency virus (strains 1 and 2).
  • the compounds may also be inhibitors of tumorogenic viruses and/or of potential use in the treatment of neoplastic diseases, i.e. cancer.
  • Compounds of the invention may be formulated for use in a pharmaceutical
  • composition which comprises a compound of formula (I) or
  • a composition which may be administered by the oral route to humans may be compounded in the form of a syrup, tablet or capsule.
  • any pharmaceutical carrier suitable for formulating such solid compositions may be used, for example magnesium stearate, starch, lactose, glucose, rice, flour and chalk.
  • the composition may also be in the form of an ingestible capsule, for example of gelatin, to contain the compound, or in the form of a syrup, a solution or a suspension.
  • Suitable liquid pharmaceutical carriers include ethyl alcohol, glycerine, saline and water to which flavouring or colouring agents may be added to form syrups.
  • the compounds may also be presented with a sterile liquid carrier for injection.
  • composition may also be formulated for topical application to the skin or eyes.
  • the composition may be in the form of a cream, lotion or ointment
  • These formulations may be conventional formulations well known in the art, for example, as described in standard books of pharmaceutics and cosmetics, such as Harry's Cosmeticology published by Leonard Hill Books and the British Pharmacopaeia.
  • composition for application to the eyes may be a conventional eye-drop
  • composition well known in the art, or an ointment composition.
  • the composition of this invention is in unit dosage form or in some other form that may be administered in a single dose.
  • a suitable dosage unit might contain from 50 mg to 1 g of active ingredient for example 100 to 500 mg.
  • Such doses may be administered 1 to 4 times a day or more usually 2 or 3 times a day.
  • the effective dose of compound will in general be in the range of from 1.0 to 20 mg/kg of body weight per day or more usually 2.0 to 10 mg/kg per day.
  • the invention also provides a method of treating viral infections/diseases in a human or non-human animal, which comprises administering to the animal an effective, non-toxic amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance, in particular for the treatment of viral infections/diseases.
  • the compounds of the invention are also believed to exhibit a synergistic antiviral effect in conjunction with interferons; and combination products comprising these two components for sequential or concomitant administration, by the same or different routes, are therefore within the ambit of the present invention.
  • the following examples illustrate the invention.
  • the resulting phosphonyl dichloridate derivative was suspended in dry dichloromethane (10ml), the appropriate alcohol (3.045mmol) was added and the solution was cooled to 0°-3°C under argon. The reaction mixture was then treated with triethylamine (3;625mmol) followed by 1-methylimidazole (5.8mmol), stirred at 0° -3°C for 10min and then at RT for 1.5h. The precipitate was filtered, washed with dichloromethane and the solvents were

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Oncology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Communicable Diseases (AREA)
  • Virology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

On décrit des composés de formule (I) ou un de leurs sels pharmaceutiques acceptables. Dans ladite formule (I) X représente -CH2O, -CH2 ou -CH(CH2OR6)O où R6 représente hydrogène ou acyle; Y représente O ou S; R1 représente hydroxy ou amino; R2 représente amino ou hydrogène; R3 représente hydrogène ou, quand X représente CH2O et Y représente O, R3 peut représenter CH2OR7 où R7 représente hydrogène ou acyle; et R4 et R5 représentent chacun phényle, 4-bromophényle, 4-méthylphényle, 4-méthoxyphényle, 2-acétoxyphényle ou 2-méthylphényle. On décrit aussi leur utilisation pharmaceutique dans le traitement des maladies virales.
PCT/GB1993/000560 1992-03-18 1993-03-18 Derives acides phosphoniques antiviraux d'analogues de purine WO1993019075A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP93906699A EP0631583A1 (fr) 1992-03-18 1993-03-18 Derives acides phosphoniques antiviraux d'analogues de purine
JP5516084A JPH07504666A (ja) 1992-03-18 1993-03-18 プリン類似化合物の抗ウイルス性ホスホン酸誘導体
KR1019940703269A KR950701638A (ko) 1992-03-18 1993-03-18 푸린 동족체의 항비루스성 포스폰산 유도체(Antiviral phosphonic acid derivatives of purine analogues)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB929205917A GB9205917D0 (en) 1992-03-18 1992-03-18 Pharmaceuticals
GB9205917.9 1992-03-18

Publications (1)

Publication Number Publication Date
WO1993019075A1 true WO1993019075A1 (fr) 1993-09-30

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1993/000560 WO1993019075A1 (fr) 1992-03-18 1993-03-18 Derives acides phosphoniques antiviraux d'analogues de purine

Country Status (7)

Country Link
EP (1) EP0631583A1 (fr)
JP (1) JPH07504666A (fr)
KR (1) KR950701638A (fr)
AU (1) AU3760793A (fr)
CA (1) CA2132303A1 (fr)
GB (1) GB9205917D0 (fr)
WO (1) WO1993019075A1 (fr)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7193081B2 (en) 2002-05-13 2007-03-20 Metabasis Therapeutics, Inc. Process for preparation of cyclic prodrugs of PMEA and PMPA
US7214668B2 (en) 2002-05-13 2007-05-08 Metabasis Therapeutics, Inc. Phosphonic acid based prodrugs of PMEA and its analogues
US7582758B2 (en) 2004-06-08 2009-09-01 Metabasis Therapeutics, Inc. Lewis acid mediated synthesis of cyclic esters
US8101745B2 (en) 2004-12-16 2012-01-24 The Regents Of The University Of California Lung-targeted drugs
US9593137B2 (en) 2011-12-22 2017-03-14 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
US9775852B2 (en) 2013-03-15 2017-10-03 The Regents Of The University Of California Acyclic nucleoside phosphonate diesters
US9801884B2 (en) 2014-09-15 2017-10-31 The Regents Of The University Of California Nucleotide analogs
US9908908B2 (en) 2012-08-30 2018-03-06 Jiangsu Hansoh Pharmaceutical Co., Ltd. Tenofovir prodrug and pharmaceutical uses thereof
US9994600B2 (en) 2014-07-02 2018-06-12 Ligand Pharmaceuticals, Inc. Prodrug compounds and uses therof
US10377782B2 (en) 2015-09-15 2019-08-13 The Regents Of The University Of California Nucleotide analogs
US10449210B2 (en) 2014-02-13 2019-10-22 Ligand Pharmaceuticals Inc. Prodrug compounds and their uses
US11970482B2 (en) 2018-01-09 2024-04-30 Ligand Pharmaceuticals Inc. Acetal compounds and therapeutic uses thereof
US12329768B2 (en) 2022-07-21 2025-06-17 Antiva Biosciences, Inc. Compositions and dosage forms for treatment of HPV infection and HPV-induced neoplasia

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0319228A2 (fr) * 1987-11-30 1989-06-07 Beecham Group Plc Composés
EP0353955A2 (fr) * 1988-08-02 1990-02-07 Beecham Group Plc Composés chimiques
EP0399743A1 (fr) * 1989-05-25 1990-11-28 Beecham Group Plc Dérivées de phosphonométhylthio-alkoxypurines, produits intermédiaires pour leurs préparation et composition pharmaceutiques les contenants
CA2051239A1 (fr) * 1990-09-14 1992-03-15 John Edward Starrett Jr. Promedicaments a base de phosphonates

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0319228A2 (fr) * 1987-11-30 1989-06-07 Beecham Group Plc Composés
EP0353955A2 (fr) * 1988-08-02 1990-02-07 Beecham Group Plc Composés chimiques
EP0399743A1 (fr) * 1989-05-25 1990-11-28 Beecham Group Plc Dérivées de phosphonométhylthio-alkoxypurines, produits intermédiaires pour leurs préparation et composition pharmaceutiques les contenants
CA2051239A1 (fr) * 1990-09-14 1992-03-15 John Edward Starrett Jr. Promedicaments a base de phosphonates

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7193081B2 (en) 2002-05-13 2007-03-20 Metabasis Therapeutics, Inc. Process for preparation of cyclic prodrugs of PMEA and PMPA
US7214668B2 (en) 2002-05-13 2007-05-08 Metabasis Therapeutics, Inc. Phosphonic acid based prodrugs of PMEA and its analogues
US7582758B2 (en) 2004-06-08 2009-09-01 Metabasis Therapeutics, Inc. Lewis acid mediated synthesis of cyclic esters
US8101745B2 (en) 2004-12-16 2012-01-24 The Regents Of The University Of California Lung-targeted drugs
US8318700B2 (en) 2004-12-16 2012-11-27 The Regents Of The University Of California Lung-targeted drugs
US10035814B2 (en) 2011-12-22 2018-07-31 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
US12398162B2 (en) 2011-12-22 2025-08-26 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
US9593137B2 (en) 2011-12-22 2017-03-14 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
US10562926B2 (en) 2011-12-22 2020-02-18 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
US11279720B2 (en) 2011-12-22 2022-03-22 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
US9908908B2 (en) 2012-08-30 2018-03-06 Jiangsu Hansoh Pharmaceutical Co., Ltd. Tenofovir prodrug and pharmaceutical uses thereof
US10076533B2 (en) 2013-03-15 2018-09-18 The Regents Of The University Of California Acyclic nucleoside phosphonate diesters
US9775852B2 (en) 2013-03-15 2017-10-03 The Regents Of The University Of California Acyclic nucleoside phosphonate diesters
US10195222B2 (en) 2013-03-15 2019-02-05 The Regents Of The University Of California Acyclic nucleoside phosphonate diesters
US10076532B2 (en) 2013-03-15 2018-09-18 The Regents Of The University Of California Acyclic nucleoside phosphonate diesters
US10449207B2 (en) 2013-03-15 2019-10-22 The Regents Of The University Of California Acyclic nucleoside phosphonate diesters
US11278559B2 (en) 2014-02-13 2022-03-22 Ligand Pharmaceuticals Incorporated Prodrug compounds and their uses
US10449210B2 (en) 2014-02-13 2019-10-22 Ligand Pharmaceuticals Inc. Prodrug compounds and their uses
US10150788B2 (en) 2014-07-02 2018-12-11 Ligand Pharmaceuticals, Inc. Prodrug compounds and uses thereof
US9994600B2 (en) 2014-07-02 2018-06-12 Ligand Pharmaceuticals, Inc. Prodrug compounds and uses therof
US9801884B2 (en) 2014-09-15 2017-10-31 The Regents Of The University Of California Nucleotide analogs
US10702532B2 (en) 2014-09-15 2020-07-07 The Regents Of The University Of California Nucleotide analogs
US11344555B2 (en) 2014-09-15 2022-05-31 The Regents Of The University Of California Nucleotide analogs
US12350274B2 (en) 2014-09-15 2025-07-08 The Regents Of The University Of California Nucleotide analogs
US10213430B2 (en) 2014-09-15 2019-02-26 The Regents Of The University Of California Nucleotide analogs
US11014950B2 (en) 2015-09-15 2021-05-25 The Regents Of The University Of California Nucleotide analogs
US10377782B2 (en) 2015-09-15 2019-08-13 The Regents Of The University Of California Nucleotide analogs
US11572377B2 (en) 2015-09-15 2023-02-07 The Regents Of The University Of California Nucleotide analogs
US11970482B2 (en) 2018-01-09 2024-04-30 Ligand Pharmaceuticals Inc. Acetal compounds and therapeutic uses thereof
US12329768B2 (en) 2022-07-21 2025-06-17 Antiva Biosciences, Inc. Compositions and dosage forms for treatment of HPV infection and HPV-induced neoplasia

Also Published As

Publication number Publication date
AU3760793A (en) 1993-10-21
KR950701638A (ko) 1995-04-28
EP0631583A1 (fr) 1995-01-04
JPH07504666A (ja) 1995-05-25
GB9205917D0 (en) 1992-04-29
CA2132303A1 (fr) 1993-09-30

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